The compound 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine of general formula (I):
also known by the name zopiclone, is a commercial product characterized for its hypnotic, sedative, tranquilizing, anxiolytic, muscle-relaxant and anticonvulsant properties. This compound was described for the first time in French patent document FR2166314, which also describes a process for obtaining it as well as pharmaceutical compositions comprising said active ingredient.
The compound of formula (I) has an asymmetric carbon atom at the 5-position of the 5H-pyrrolo[3,4-b]pyrazine ring-system and, as a result, it must be considered, in racemic form, to consist of an equimolecular mixture of the laevorotatory and dextrorotatory forms. In a racemic product, it is widely known that, often, one of the two enantiomers is active and that an enhancement of the toxicity may be linked to this activity, the other enantiomer being both markedly less active or inactive and less toxic.
In the case of zopiclone, it was found that the dextrorotatory enantiomer (S-enantiomer) is approximately twice active as the racemate, while having a lower toxicity than that of the racemate, but that the laevorotatory isomer is both almost inactive and more toxic than the racemate.
The dextrorotatory isomer of zopiclone, also known as eszopiclone, may be prepared from the corresponding racemate according to usual methods, such as chiral-phase chromatography, resolution of an optically active salt, stereoselective enzymatic catalysis by means of an appropriate microorganism, or asymmetric synthesis.
The first reference describing a process for obtaining the different enantiomers of zopiclone is EP0609210. More specifically, this document refers to a process for obtaining the dextrorotatory isomer of zopiclone by resolution of racemic zopiclone by using an optically active acid, namely D-(+)-O,O′-dibenzoyl-tartaric acid, working in the presence of an appropriate organic solvent, isolating the salt of the dextrorotatory isomer, displacing this isomer from its salt and optionally, the conversion of said isomer into a pharmaceutically acceptable salt.
The scientific publication Chirality, 5, 419 (1993) and international applications WO2005/079851, WO2005/060968 and WO2005/097132 describe the resolution of the racemic mixture of zopiclone to afford eszopiclone by using malic acid as optically active acid in the presence of a mixture of acetone and methanol as organic solvents. The resulting (S)-zopiclone D-malate salt is converted to optically pure eszopiclone by treatment with aqueous potassium carbonate and ethyl acetate, followed by separation, crystallization and milling to the desired size.
The American patent application US2007/054914 refers to a method for the resolution of the racemic mixture of zopiclone by using di-p-toluoyl tartaric acid as optically active acid.
However, in spite of the existence of processes allowing the resolution of racemic zopiclone by fractionated crystallization using classic resolving agents, more specifically chiral acids, such as malic, dibenzoyltartaric and di-p-toluoyl tartaric acids, in organic solvents, these lead to compounds with low optical purity in a single crystallization and little reproducibility, what it makes necessary further crystallization processes to obtain high optical purities. Consequently, there is a serious need to develop improved processes which allows obtaining enantiomers of a higher optical purity.